Glioblastoma multiforme (GBM) is a malignant primary brain tumor affecting about 12,000 new cases per year in the U.S. Average survival is only about 14-15 months. Radiation (RT) is most commonly administered as 30 fractions of 2 Gray each over 6-weeks with concomitant temozolomide (TMZ). GBM tumors are hypoxic. The primary mechanism of RT is creation of singlet oxygen; hypoxia within GBM adversely affects response to RT and decreases survival. NVX-108 dodecafluoropentane emulsion (DDFPe) transports over 100x as much O2 per gram of fluorocarbon (FC) than higher MW FC (e.g. Fluosol and perfluorooctylbromide) previously studied as O2 therapeutics which failed. NVX-108 clears via exhalation with a terminal half-life in humans of about 90 minutes. In tumor xenografts NVX+108 significantly increases tumor pO2 with a duration of effect > two hours following IV administration. Animal tumor models show improved survival with NVX-108 + RT versus RT alone. NVX-108 is presently being tested as a radiosensitizer in patients with GBM ? administered prior to each fraction of RT with concomitant TMZ. In this trial we are obtaining gene profiling on tumor specimens and TOLD MRI to evaluate tumor O2 pre and post NVX-108. The drug is safe, there is evidence of tumor re- oxygenation on TOLD MRI and therapeutic efficacy. The first patient (TMZ non-responder) survived 21- months. The second patient is alive at 21-months (TMZ responder) but was 65-years of age at diagnosis; a (patients 65-years of age and older only have predicted survival of about 9-months). All other patients are currently alive (11 treated to date). DDFPe was previously tested as an ultrasound contrast agent in 2,200 patients. NuvOx licensed the patents and obtained ownership of the regulatory documents for DDFPe. The FDA has agreed that NuvOx can reference these documents in support of development of NVX-108. The FDA will regulate NVX-108 as a Biologic. Regulation as a Biologic confers 12 years of exclusivity for a first in class indication. NuvOx has received Orphan Drug Designation for NVX-108 for glioblastoma. Specific Aim 1. To file an IND for a randomized, prospective placebo-controlled trial of NVX-108 to treat GBM. Specific Aim 2. Conduct randomized, placebo controlled trial of NVX-108 in chemoradiation of GBM. Experimental design: Patients will be randomized 1:1 to placebo + O2 breathing or IV infusion of NVX-108 + O2 breathing prior to each fraction of RT (2Gy per fraction, 30 fractions over 6-weeks with concomitant TMZ). The initiation of the Phase II trial will occur at the University of Arizona, Barrow Neurological Institute (BNI) the Miami Cancer Institute and Banner MD Anderson. In addition, patients will undergo TOLD MRI to assess tumor O2. Otherwise, patients will have standard of care therapy and standard follow-up. Depending upon accrual and other factors we plan to initiate additional sites. Expected outcome: Successful completion of the Aims proposed in this study should confirm that NVX-108 re-oxygenates GBM and show improved survival in association with treatment with chemoradiation.